PROJECT SUMMARY/ABSTRACT The purpose of this R61/R33 project is to determine and optimize the neural mechanisms supporting mindfulness-based pain relief in rheumatoid arthritis (RA) patients. The scientific premise is that RA patients? use of an elemental mindfulness meditation practice?mindful breathing (MB)?and a positive emotion generative practice?savoring (SAV)?during noxious thermal stimulation will alter activation in the corticostriatal circuits. Further, an intervention that combines MB and SAV?mindful savoring (MB+SAV)--will optimize corticostriatal engagement and improve RA clinical outcomes. The corticostriatal circuits are attractive neural mechanisms of the putative benefits of mindfulness for RA because directly support cognitive appraisals of aversive stimuli and reward valuation, which are behavioral targets of our interventions. Target corticostriatal regions include the lateral orbitofrontal cortex (LOFC), which supports top-down control of attention and emotional appraisals, and the nucleus accumbens (NAc), which supports positive emotion regulation and reward appraisals. The behavioral output of the corticostriatal circuits is especially relevant for patients with RA, due to the flaring, unpredictable nature of RA pain and the importance of positive emotional function for RA pain coping. In the R61 phase, we will randomize RA patients to a brief 4-session (20-25 minutes each) course of MB (n=20), SAV (n=20), or a sham MB control (n=20). At post-intervention, participants will undergo functional MRI (fMRI) using a perfusion-based arterial spin labeling (ASL) technique during noxious thermal stimulation to determine if MB and SAV are associated with corticostriatal activation when compared to rest, as well as a Sham MB control. In the R33 phase we will randomize RA patients to 4 sessions of MB (n=30), SAV (n=30), or MB+SAV (n=30). Pre- and post-intervention ASL scans will be obtained using the same protocol as in the R61. Additionally, the secondary clinical outcomes of pain severity, unpleasantness and interference, disease activity, and fatigue will be obtained at pre-intervention, post-intervention, and weekly for 3 months. We propose that MB will increase cerebral blood flow (CBF) in the lOFC during noxious thermal stimulation, and SAV will decrease CBF in the NAc, relative to the CBF response to noxious stimulation during rest. We further propose that MB+SAV will optimize engagement of both regions to a greater extent than either MB or SAV alone. We expect that optimizing the engagement of the lOFC and NAc will be associated with improved RA clinical outcomes. Our approach will identify reproducible mechanisms and link them to RA chronic pain outcomes. Our interventions will be ready to disseminate because they are brief and require minimal provider contact. Our results will inform the development of new mindfulness intervention protocols that are guided by neural mechanisms, thereby increasing the efficiency and precision with which they are applied to patients with RA.